Ivosenib 250 mg (Ivosidenib)

Description

COMPOSITION
IVOSENIB tablet: Each film coated tablet contains Ivosidenib INN
250 mg.
PHARMACOLOGY
Mechanism of Action
Ivosidenib is a small molecule inhibitor that targets the mutant
isocitrate dehydrogenase 1 (IDH1) enzyme. In patients with AML,
susceptible IDH1 mutations are defined as those leading to
increased levels of 2-hydroxyglutarate (2-HG) in the leukemia cells
and where efficacy is predicted by 1) clinically meaningful remissions
with the recommended dose of Ivosidenib and/or 2) inhibition of
mutant IDH1 enzymatic activity at concentrations of Ivosidenib
sustainable at the recommended dosage according to validated
methods. The most common of such mutations in patients with AML
are R132H and R132C substitutions.
Ivosidenib was shown to inhibit selected IDH1 R132 mutants at much
lower concentrations than wild-type IDH1 in vitro. Inhibition of the
mutant IDH1 enzyme by Ivosidenib led to decreased 2HG levels and
induced myeloid differentiation in vitro and in vivo in mouse xenograft
models of IDH1-mutated AML. In blood samples from patients with
AML with mutated IDH1, Ivosidenib decreased 2-HG levels ex-vivo,
reduced blast counts, and increased percentages of mature myeloid
cells. In a patient-derived xenograft intra-hepatic cholangiocarcinoma
mouse model with IDH1 R132C, Ivosidenib reduced 2-HG levels.
Pharmacokinetics
The following Ivosidenib pharmacokinetic parameters were observed
following administration of Ivosidenib 500 mg as a single dose or
daily dose (for steady-state), unless otherwise specified. The
steady-state pharmacokinetics of Ivosidenib 500 mg were compara-
ble between patients with newly diagnosed AML, relapsed or
refractory AML, and cholangiocarcinoma.
In patients with AML, the mean (%CV) peak plasma concentration
(Cmax) is 4,503 ng/mL (38%) after a single dose, and 6,551 ng/mL
(44%) at steady-state. The mean steady-state area under the
concentration time curve (AUC) is 117,348 ng•hr/mL (50%). In
patients with cholangiocarcinoma, the mean Cmax is 4,060 ng/mL
(45%) after a single dose, and 4,799 ng/mL (33%) at steady-state.
The mean steady-state AUC is 86,382 ng•hr/mL (34%).
Absorption
The median time to Cmax is approximately 3 hours in patients with
AML and 2 hours in patients with cholangiocarcinoma.
Effect of Food
Following administration of a single dose in healthy subjects, a
high-fat meal (approximately 900 to 1,000 calories, 500 to 600 fat
calories, 250 carbohydrate calories and 150 protein calories)
increased Ivosidenib Cmax by 98% (90% CI: 79%, 119%) and
AUCinf by approximately 25%.
Distribution
The mean (%CV) apparent central volume of distribution (Vc/F) of
Ivosidenib at steady-state is 234 L (47%) in patients with AML and
222 L (26%) in patients with cholangiocarcinoma. Protein binding of
Ivosidenib ranges from 92 to 96% in vitro